Joaquín Espinosa, PhD, director of the Linda Crnic Institute for Down Syndrome. Photo courtesy of the Global Down Syndrome Foundation.
By Mark Couch
(May 2018) Researchers from the University of Colorado School of Medicine are
conducting breakthrough research indicating that Down syndrome could be
considered a disorder of the immune system.
announced in the journals eLife and Scientific Reports are a significant
development in understanding Down syndrome.
syndrome has been classified as a mental disorder, as an intellectual
disability, as a brain condition,” said Joaquín Espinosa, PhD, director
of the Linda Crnic Institute for Down Syndrome at the CU Anschutz
Medical Campus. “And that’s fine, those are all fair labels. But you can
also understand Down syndrome under a different light.”
In between meetings with his laboratory’s researchers on a busy day last January, Espinosa rattled through a list:
- “You can say that Down syndrome is a genetic condition where people are protected from solid cancers.
- “You can say that people with Down syndrome are the largest human
population with a predisposition to autoimmune disorders – 30 percent –
celiac disease, autoimmune hypothyroidism, type 1 diabetes, autoimmune
skin conditions, rheumatoid arthritis.
- “People with
Down syndrome are the largest human population with a genetic
predisposition to early-onset Alzheimer’s disease – 100 percent.”
Joaquín Espinosa, PhD, director of the Linda Crnic Institute for
Down Syndrome, and a guest posing at the Global Down Syndrome
Foundation's annual Be Beautiful Be Yourself fashion show.
Photo courtesy the Global Down Syndrome Foundation
he ties together the conditions on the list: “So Down syndrome is many
things,” Espinosa said, “and then when you put every one of those
through the prism of an immune disorder, it makes sense every time.”
Sie Whitten, president and CEO of the Global Down Syndrome Foundation,
which has funded Espinosa’s research, called the work a “game-changing
That discovery is now the foundation for a scientific program that could have health benefits for all.
one of those beautiful scientific journeys, where we just followed the
data, followed the science and it may take you places you didn’t want to
go or to places you didn’t anticipate you were going to go,” Espinosa
For Espinosa, that is certainly true. A cancer
biologist, he was recruited CU Boulder in 2004 and he continues to serve
as co-leader of the CU Cancer Center’s molecular oncology program. But
along the way, he applied for a grant offered by the Crnic Institute.
Crnic Institute had recruited Dr. Tom Blumenthal as executive director,
who was my chair in Boulder,” Espinosa said. “What he did was create a
grant program for scientists who were within the University of Colorado.
I applied. I knew Tom very well and I wanted him to do well. I was
super busy at the time with my cancer research. I didn’t necessarily
have an interest in Down syndrome, but I thought OK, this seems like a
good opportunity to start a new line of research.”
project opened a new path in Espinosa’s career, first as associate
director for science at the Crnic Institute since 2015 and now as its
executive director since July 2017.
“I’m not an
immunologist. In fact, to some degree I was trying to stay away from
immunology. I think it’s so complex and sophisticated and I had my plate
full with the complexity of cancer biology. But the data from that
first grant and from experiments we did afterwards, and from other
experiments that other people in the Crnic Institute were doing, started
converging – dysregulation of the immune system in people with Down
“And now this has become the centerpiece of a
research program, trying to understand how this immune dysregulation
contributes to the many facets of Down syndrome.”
the immune system to fight cancer has been intensified focus of
researchers for decades, but they also know that an out-of-control
autoimmune system has detrimental effects.
Joaquín Espinosa, PhD, and advocates representing the Global Down
Syndrome Foundation. Photo courtesy the Global Down Syndrome
sense that a person who has a hyper-activated antiviral response will
have a tendency to autoimmune conditions,” Espinosa said. “The
interferon pathway, the same set of molecules that we use to fight
viruses, when deregulated, will give you an autoimmune condition because
basically they attack healthy cells.”
health conditions, such as leukemia congenital heart defects, that can
result from overactive autoimmune systems and that are more common among
people with Down syndrome. Additionally, hyper-activation of the immune
system in the brain is toxic, killing neurons.
the dots, though, is much harder than it sounds and more work needs to
be done before safety and efficiency of any therapies can be determined.
“It is simple in concept, although technologically quite
an amazing feat,” Espinosa said. “We did a functional genomics
approach, meaning you measure thousands and thousands of genes or
thousands and thousands of proteins and hundreds of metabolites. You’re
taking a lot of measurements. It’s difficult in practice, but simple in
The Human Trisome Project at the Linda Crnic Institute
is designed to be the largest and most comprehensive study of why
individuals with Down syndrome, also called trisomy 21, are protected
from some health conditions, such as cancer, while highly predisposed to
others, such as Alzheimer’s disease. For the project, the research team
is recruiting persons between 6 months and 89 years old, with or
without Down syndrome.
“You’re looking at as much as you
can, casting a big net and then asking, ‘What are the things that are
different in people with Down syndrome relative to our control group of
individuals that don’t have Down syndrome but as far as we can tell they
don’t have any other differential variable in the control group?’ When
we do that, in every case, at the top of the chart is the immune system
and specific aspects of the immune system. “
identifying the potential source of concern, options for therapies can
be considered. One way is to consider how the human body naturally
blocks interferon, proteins that activate usually to respond to a virus
or other pathogen. The Crnic Institute is looking at proteins that
neutralize interferon and developing experiments to study them.
a good map and charting the multiple paths is a daunting task that will
require help from many supporters. Supporters include the Global Down
Syndrome Foundation, the Anna and John J. Sie Foundation, the School of
Medicine and Biogen.
Historically, the primary federal
agency providing funding research on Down syndrome has been the National
Institute of Child Health and Human Development because the syndrome
was originally cast as a pediatric condition. But today, people with
Down syndrome commonly live into adulthood, with some living into their
Espinosa hopes to build on the understanding that
there are health benefits for all that can result from the Crnic
Institute’s work and that deserve support from other federal agencies.
Earlier this year, U.S. Rep. Mike Coffman, who represents the
congressional district that includes the Anschutz Medical Campus,
introduced legislation directing the U.S. Department of Veterans’
Affairs to establish Alzheimer’s disease research, education, and
clinical centers that include a scientific focus on the connection
between Down syndrome and Alzheimer’s disease.
we call therapeutic leverage,” Espinosa said. “As you’re trying to help
people with Down syndrome, you end up learning about other conditions
and most likely helping typical people with related conditions. The
immune system is everywhere in your body, so it has this power either
making trouble or fixing things for a large number of things.”